NMDAR-dependent long-term depression is associated with increased short term plasticity through autophagy mediated loss of PSD-95

• Published in: Nature communications Vol. 12; no. 1; p. 2849
• Main Authors: Compans, Benjamin, Camus, Come, Kallergi, Emmanouela, Sposini, Silvia, Martineau, Magalie, Butler, Corey, Kechkar, Adel, Klaassen, Remco V., Retailleau, Natacha, Sejnowski, Terrence J., Smit, August B., Sibarita, Jean-Baptiste, Bartol, Thomas M., Perrais, David, Nikoletopoulou, Vassiliki, Choquet, Daniel, Hosy, Eric
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 14; 14/34; 631/378/2591/2593; 631/378/548/1964; 9/74; Adenosine Triphosphate - administration & dosage; Animals; Autophagy; Autophagy - physiology; Cells, Cultured; Circuits; Cognitive science; Disks Large Homolog 4 Protein - deficiency; Disks Large Homolog 4 Protein - physiology; Female; Glutamic acid receptors; Glutamic acid receptors (ionotropic); Hippocampus - cytology; Hippocampus - physiology; Humanities and Social Sciences; In Vitro Techniques; Long-term depression; Long-Term Synaptic Depression - physiology; Male; Mice; Mice, Inbred C57BL; Miniature Postsynaptic Potentials - physiology; Models, Neurological; Molecular modelling; multidisciplinary; N-Methyl-D-aspartic acid receptors; N-Methylaspartate - administration & dosage; Neuronal Plasticity - physiology; Neurons - cytology; Neurons - drug effects; Neurons - physiology; Neuroscience; Phagocytosis; Plastic properties; Plasticity; Postsynaptic density proteins; Rats; Rats, Sprague-Dawley; Receptors, AMPA - physiology; Receptors, N-Methyl-D-Aspartate - physiology; Receptors, Purinergic P2X - physiology; Science; Science (multidisciplinary); Synapses; Synaptic strength; Synaptogenesis; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23133-9

Long-term depression (LTD) of synaptic strength can take multiple forms and contribute to circuit remodeling, memory encoding or erasure. The generic term LTD encompasses various induction pathways, including activation of NMDA, mGlu or P2X receptors. However, the associated specific molecular mechanisms and effects on synaptic physiology are still unclear. We here compare how NMDAR- or P2XR-dependent LTD affect synaptic nanoscale organization and function in rodents. While both LTDs are associated with a loss and reorganization of synaptic AMPARs, only NMDAR-dependent LTD induction triggers a profound reorganization of PSD-95. This modification, which requires the autophagy machinery to remove the T19-phosphorylated form of PSD-95 from synapses, leads to an increase in AMPAR surface mobility. We demonstrate that these post-synaptic changes that occur specifically during NMDAR-dependent LTD result in an increased short-term plasticity improving neuronal responsiveness of depressed synapses. Our results establish that P2XR- and NMDAR-mediated LTD are associated to functionally distinct forms of LTD. Long-term depression (LTD) of synaptic strength contributes to circuit remodeling, memory encoding and erasure. Here, the authors show that P2XR- and NMDAR-dependent LTD are associated with distinct and precise molecular modifications that lead to specific modification of synapse function.